Pyrazole compounds useful as protein kinase inhibitors

ABSTRACT

This invention describes novel pyrazole compounds of formula II: 
                         
wherein Z 1  is nitrogen or CR 8 ; Q is —S—, —O—, —N(R 4 )—, or —CH(R 6 )—; R 1  is T-Ring D, wherein Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl; and R y , R 2 , and R 2′  are as described in the specification. The compounds are useful as protein kinase inhibitors, especially as inhibitors of Aurora-2 and GSK-3, for treating diseases such as cancer, diabetes and Alzheimer&#39;s disease.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.10/034,019, filed Dec. 20, 2001, now U.S. Pat. No. 6,727,251, whichclaims priority to U.S. Provisional Application Ser. No. 60/257,887filed Dec. 21, 2000 and U.S. Provisional Application Ser. No. 60/286,949filed Apr. 27, 2001, the entirety of which is incorporated herein byreference.

FIELD OF THE INVENTION

The present invention is in the field of medicinal chemistry and relatesto compounds that are protein kinase inhibitors, compositions containingsuch compounds and methods of use. More particularly, this inventionrelates to compounds that are inhibitors of Aurora-2 protein kinase. Theinvention also relates to methods of treating diseases associated withprotein kinases, especially diseases associated with Aurora-2, such ascancer.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly aided in recentyears by better understanding of the structure of enzymes and otherbiomolecules associated with target diseases. One important class ofenzymes that has been the subject of extensive study is the proteinkinases.

Protein kinases mediate intracellular signal transduction. They do thisby effecting a phosphoryl transfer from a nucleoside triphosphate to aprotein acceptor that is involved in a signaling pathway. There are anumber of kinases and pathways through which extracellular and otherstimuli cause a variety of cellular responses to occur inside the cell.Examples of such stimuli include environmental and chemical stresssignals (e.g. osmotic shock, heat shock, ultraviolet radiation,bacterial endotoxin, H₂O₂), cytokines (e.g. interleukin-1 (IL-1) andtumor necrosis factor α (TNF-α)), and growth factors (e.g. granulocytemacrophage-colony-stimulating factor (GM-CSF), and fibroblast growthfactor (FGF). An extracellular stimulus may effect one or more cellularresponses related to cell growth, migration, differentiation, secretionof hormones, activation of transcription factors, muscle contraction,glucose metabolism, control of protein synthesis and regulation of cellcycle.

Many diseases are associated with abnormal cellular responses triggeredby protein kinase-mediated events. These diseases include autoimmunediseases, inflammatory diseases, neurological and neurodegenerativediseases, cancer, cardiovascular diseases, allergies and asthma,Alzheimer's disease or hormone-related diseases. Accordingly, there hasbeen a substantial effort in medicinal chemistry to find protein kinaseinhibitors that are effective as therapeutic agents.

Aurora-2 is a serine/threonine protein kinase that has been implicatedin human cancer, such as colon, breast and other solid tumors. Thiskinase is believed to be involved in protein phosphorylation events thatregulate the cell cycle. Specifically, Aurora-2 may play a role incontrolling the accurate segregation of chromosomes during mitosis.Misregulation of the cell cycle can lead to cellular proliferation andother abnormalities. In human colon cancer tissue, the aurora-2 proteinhas been found to be overexpressed. See Bischoff et al., EMBO J., 1998,17, 3052-3065; Schumacher et al., J. Cell Biol., 1998, 143, 1635-1646;Kimura et al., J. Biol. Chem., 1997, 272, 13766-13771.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinasecomprised of α and β isoforms that are each encoded by distinct genes[Coghlan et al., Chemistry & Biology, 7, 793-803 (2000); Kim and Kimmel,Curr. Opinion Genetics Dev., 10, 508-514 (2000)]. GSK-3 has beenimplicated in various diseases including diabetes, Alzheimer's disease,CNS disorders such as manic depressive disorder and neurodegenerativediseases, and cardiomyocete hypertrophy [WO 99/65897; WO 00/38675; andHaq et al., J. Cell Biol. (2000) 151, 117]. These diseases may be causedby, or result in, the abnormal operation of certain cell signalingpathways in which GSK-3 plays a role. GSK-3 has been found tophosphorylate and modulate the activity of a number of regulatoryproteins. These proteins include glycogen synthase which is the ratelimiting enzyme necessary for glycogen synthesis, the microtubuleassociated protein Tau, the gene transcription factor β-catenin, thetranslation initiation factor e1F2B, as well as ATP citrate lyase, axin,heat shock factor-1, c-Jun, c-Myc, c-Myb, CREB, and CEPBα. These diverseprotein targets implicate GSK-3 in many aspects of cellular metabolism,proliferation, differentiation and development.

In a GSK-3 mediated pathway that is relevant for the treatment of typeII diabetes, insulin-induced signaling leads to cellular glucose uptakeand glycogen synthesis. Along this pathway, GSK-3 is a negativeregulator of the insulin-induced signal. Normally, the presence ofinsulin causes inhibition of GSK-3 mediated phosphorylation anddeactivation of glycogen synthase. The inhibition of GSK-3 leads toincreased glycogen synthesis and glucose uptake [Klein et al., PNAS, 93,8455-9 (1996); Cross et al., Biochem. J., 303, 21-26 (1994); Cohen,Biochem. Soc. Trans., 21, 555-567 (1993); Massillon et al., Biochem J.299, 123-128 (1994)]. However, in a diabetic patient where the insulinresponse is impaired, glycogen synthesis and glucose uptake fail toincrease despite the presence of relatively high blood levels ofinsulin. This leads to abnormally high blood levels of glucose withacute and long term effects that may ultimately result in cardiovasculardisease, renal failure and blindness. In such patients, the normalinsulin-induced inhibition of GSK-3 fails to occur. It has also beenreported that in patients with type II diabetes, GSK-3 is overexpressed[WO 00/38675]. Therapeutic inhibitors of GSK-3 are therefore potentiallyuseful for treating diabetic patients suffering from an impairedresponse to insulin.

GSK-3 activity has also been associated with Alzheimer's disease. Thisdisease is characterized by the well-known β-amyloid peptide and theformation of intracellular neurofibrillary tangles. The neurofibrillarytangles contain hyperphosphorylated Tau protein where Tau isphosphorylated on abnormal sites. GSK-3 has been shown to phosphorylatethese abnormal sites in cell and animal models. Furthermore, inhibitionof GSK-3 has been shown to prevent hyperphosphorylation of Tau in cells[Lovestone et al., Current Biology 4, 1077-86 (1994); Brownlees et al.,Neuroreport 8, 3251-55 (1997)]. Therefore, it is believed that GSK-3activity may promote generation of the neurofibrillary tangles and theprogression of Alzheimer's disease.

Another substrate of GSK-3 is β-catenin which is degradated afterphosphorylation by GSK-3. Reduced levels of β-catenin have been reportedin schizophrenic patients and have also been associated with otherdiseases related to increase in neuronal cell death [Zhong et al.,Nature, 395, 698-702 (1998); Takashima et al., PNAS, 90, 7789-93 (1993);Pei et al., J. Neuropathol. Exp, 56, 70-78 (1997)].

As a result of the biological importance of GSK-3, there is currentinterest in therapeutically effective GSK-3 inhbitors. Small moleculesthat inhibit GSK-3 have recently been reported [WO 99/65897 (Chiron) andWO 00/38675 (SmithKline Beecham)].

For many of the aforementioned diseases associated with abnormal GSK-3activity, other protein kinases have also been targeted for treating thesame diseases. However, the various protein kinases often act throughdifferent biological pathways. For example, certain quinazolinederivatives have been reported recently as inhibitors of p38 kinase (WO00/12497 to Scios). The compounds are reported to be useful for treatingconditions characterized by enhanced p38-α activity and/or enhancedTGF-β activity. While p38 activity has been implicated in a wide varietyof diseases, including diabetes, p38 kinase is not reported to be aconstituent of an insulin signaling pathway that regulates glycogensynthesis or glucose uptake. Therefore, unlike GSK-3, p38 inhibitionwould not be expected to enhance glycogen synthesis and/or glucoseuptake.

There is a continued need to find new therapeutic agents to treat humandiseases. The protein kinases Aurora-2 and GSK-3 are especiallyattractive targets for the discovery of new therapeutics due to theirimportant roles in cancer and diabetes, respectively.

DESCRIPTION OF THE INVENTION

It has now been found that compounds of this invention andpharmaceutical compositions thereof are effective as protein kinaseinhibitors, particularly as inhibitors of Aurora-2. These compounds havethe general formula I:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

-   Z¹ to Z⁴ are as described below;-   Ring A is selected from the group consisting of:

-   R^(x) is T-R³ or L-Z-R³;-   R^(y) is Z-R^(3′) or an optionally substituted group selected from    C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10 ring    atoms, or a heterocyclyl ring having 5-10 ring atoms, or R^(y) and    R⁸ are taken together to form a fused, optionally substituted 5-7    membered, unsaturated or partially unsaturated, ring having 0-3 ring    heteroatoms selected from nitrogen, oxygen, or sulfur;-   Q is selected from —N(R⁴)—, —O—, —S—, or —CH(R⁶)—;-   R¹ is T-(Ring D);-   Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic    ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl,    said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms    selected from nitrogen, oxygen or sulfur, wherein each substitutable    ring carbon of Ring D is independently substituted by oxo, T-R⁵, or    V-Z-R⁵, and each substitutable ring nitrogen of Ring D is    independently substituted by —R⁴;-   T is a valence bond or a C₁₋₄ alkylidene chain, wherein when Q is    —CH(R⁶)—, a methylene unit of said C₁₋₄ alkylidene chain is    optionally replaced by —O—, —S—, —N(R⁴)—, —CO—, —CONH—, —NHCO—,    —SO₂—, —SO₂NH—, —NHSO₂—, —CO₂—, —OC(O)—, —OC(O)NH—, or —NHCO₂—;-   Z is a C₁₋₄ alkylidene chain;-   L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,    —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N (R⁶)SO₂N(R⁶)—,    —N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,    —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,    —C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,    —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;-   R² and R^(2′) are independently selected from —R, -T-W—R⁶, or R² and    R^(2′) are taken together with their intervening atoms to form a    fused, 5-8 membered, unsaturated or partially unsaturated, ring    having 0-3 ring heteroatoms selected from nitrogen, oxygen, or    sulfur, wherein each substitutable ring carbon of said fused ring    formed by R² and R^(2′) is independently substituted by halo, oxo,    —CN, —NO₂, —R⁷, or —V—R⁶, and each substitutable ring nitrogen of    said ring formed by R² and R^(2′) is independently substituted by    R⁴;-   R³ is selected from —R, -halo, —OR, —C(═O)R, —CO₂R, —COCOR,    —COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,    —SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic),    —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,    —N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;-   R^(3′) is selected from -halo, —OR, —C(═O)R, —CO₂R, —COCOR,    —COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,    —SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic),    —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,    —N(R⁴)SO₂R, —OC(═O)N(R⁷)₂, or an optionally substituted group    selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having    5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;-   each R is independently selected from hydrogen or an optionally    substituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a    heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring    having 5-10 ring atoms;-   each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionally    substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;-   each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,    —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,    —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted    C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,    —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;-   V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,    —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,    —N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,    —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,    —C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,    —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;-   W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,    —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,    —C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—,    —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,    —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;-   each R⁶ is independently selected from hydrogen or an optionally    substituted C₁₋₄ aliphatic group, or two R⁶ groups on the same    nitrogen atom are taken together with the nitrogen atom to form a    5-6 membered heterocyclyl or heteroaryl ring;-   each R⁷ is independently selected from hydrogen or an optionally    substituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen are    taken together with the nitrogen to form a 5-8 membered heterocyclyl    or heteroaryl ring; and-   R⁸ is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂,    —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,    —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic),    —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,    —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂.

As used herein, the following definitions shall apply unless otherwiseindicated. The phrase “optionally substituted” is used interchangeablywith the phrase “substituted or unsubstituted” or with the term“(un)substituted.” Unless otherwise indicated, an optionally substitutedgroup may have a substituent at each substitutable position of thegroup, and each substitution is independent of the other.

The term “aliphatic” as used herein means straight-chain, branched orcyclic C₁-C₁₂ hydrocarbons which are completely saturated or whichcontain one or more units of unsaturation but which are not aromatic.For example, suitable aliphatic groups include substituted orunsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl. The terms “alkyl”, “alkoxy”, “hydroxyalkyl”,“alkoxyalkyl”, and “alkoxycarbonyl”, used alone or as part of a largermoiety includes both straight and branched chains containing one totwelve carbon atoms. The terms “alkenyl” and “alkynyl” used alone or aspart of a larger moiety shall include both straight and branched chainscontaining two to twelve carbon atoms. The term “cycloalkyl” used aloneor as part of a larger moiety shall include cyclic C₃-C₁₂ hydrocarbonswhich are completely saturated or which contain one or more units ofunsaturation, but which are not aromatic.

The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” means alkyl,alkenyl or alkoxy, as the case may be, substituted with one or morehalogen atoms. The term “halogen” means F, Cl, Br, or I.

The term “heteroatom” means nitrogen, oxygen, or sulfur and includes anyoxidized form of nitrogen and sulfur, and the quaternized form of anybasic nitrogen. Also the term “nitrogen” includes a substitutablenitrogen of a heterocyclic ring. As an example, in a saturated orpartially unsaturated ring having 0-3 heteroatoms selected from oxygen,sulfur or nitrogen, the nitrogen may be N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl).

The terms “carbocycle”, “carbocyclyl”, “carbocyclo”, or “carbocyclic” asused herein means an aliphatic ring system having three to fourteenmembers. The terms “carbocycle”, “carbocyclyl”, “carbocyclo”, or“carbocyclic” whether saturated or partially unsaturated, also refers torings that are optionally substituted. The terms “carbocycle”,“carbocyclyl”, “carbocyclo”, or “carbocyclic” also include aliphaticrings that are fused to one or more aromatic or nonaromatic rings, suchas in a decahydronaphthyl or tetrahydronaphthyl, where the radical orpoint of attachment is on the aliphatic ring.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to aromatic ring groupshaving five to fourteen members, such as phenyl, benzyl, phenethyl,1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. The term “aryl”also refers to rings that are optionally substituted. The term “aryl”may be used interchangeably with the term “aryl ring”. “Aryl” alsoincludes fused polycyclic aromatic ring systems in which an aromaticring is fused to one or more rings. Examples include 1-naphthyl,2-naphthyl, 1-anthracyl and 2-anthracyl. Also included within the scopeof the term “aryl”, as it is used herein, is a group in which anaromatic ring is fused to one or more non-aromatic rings, such as in anindanyl, phenanthridinyl, or tetrahydronaphthyl, where the radical orpoint of attachment is on the aromatic ring.

The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as used hereinincludes non-aromatic ring systems having five to fourteen members,preferably five to ten, in which one or more ring carbons, preferablyone to four, are each replaced by a heteroatom such as N, O, or S.Examples of heterocyclic rings include 3-1H-benzimidazol-2-one,(1-substituted)-2-oxo-benzimidazol-3-yl, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl,4-tetrahydropyranyl, [1,3]-dioxalanyl, [1,3]-dithiolanyl,[1,3]-dioxanyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2-thiomorpholinyl,3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl,diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl, benzoxanyl,benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, andbenzothianyl. Also included within the scope of the term “heterocyclyl”or “heterocyclic”, as it is used herein, is a group in which anon-aromatic heteroatom-containing ring is fused to one or more aromaticor non-aromatic rings, such as in an indolinyl, chromanyl,phenanthridinyl, or tetrahydroquinolinyl, where the radical or point ofattachment is on the non-aromatic heteroatom-containing ring. The term“heterocycle”, “heterocyclyl”, or “heterocyclic” whether saturated orpartially unsaturated, also refers to rings that are optionallysubstituted.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to heteroaromatic ringgroups having five to fourteen members. Examples of heteroaryl ringsinclude 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl,5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 5-tetrazolyl, 2-triazolyl, 5-triazolyl, 2-thienyl,3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl,indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl,benzimidazolyl, isoquinolinyl, indazolyl, isoindolyl, acridinyl, orbenzoisoxazolyl. Also included within the scope of the term“heteroaryl”, as it is used herein, is a group in which a heteroatomicring is fused to one or more aromatic or nonaromatic rings where theradical or point of attachment is on the heteroaromatic ring. Examplesinclude tetrahydroquinolinyl, tetrahydroisoquinolinyl, andpyrido[3,4-d]pyrimidinyl. The term “heteroaryl” also refers to ringsthat are optionally substituted. The term “heteroaryl” may be usedinterchangeably with the term “heteroaryl ring” or the term“heteroaromatic”.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) orheteroaryl (including heteroaralkyl and heteroarylalkoxy and the like)group may contain one or more substituents. Examples of suitablesubstituents on the unsaturated carbon atom of an aryl, heteroaryl,aralkyl, or heteroaralkyl group include a halogen, —R^(o), —OR^(o),—SR^(o), 1,2-methylene-dioxy, 1,2-ethylenedioxy, protected OH (such asacyloxy), phenyl (Ph), substituted Ph, —O(Ph), substituted —O(Ph),—CH₂(Ph), substituted —CH₂(Ph), —CH₂CH₂(Ph), substituted —CH₂CH₂(Ph),—NO₂, —CN, —N(R^(o))₂, —NR^(o)C(O)R^(o), —NR^(o)C(O)N(R^(o))₂,—NR^(o)CO₂R^(o), —NR^(o)NR^(o)C(O)R^(o), —NR^(o)NR^(o)C(O)N(R^(o))₂,—NR^(o)NR^(o)CO₂R^(o), —C(O)C(O)R^(o), —C(O)CH₂C(O)R^(o), —CO₂R^(o),—C(O)R^(o), —C(O)N(R^(o))₂, —OC(O)N(R^(o))₂, —S(O)₂R^(o), —SO₂N(R^(o))₂,—S(O)R^(o), —NR^(o)SO₂N(R^(o))₂, —NR^(o)SO₂R^(o), —C(═S)N(R^(o))₂,—C(═NH)—N(R^(o))₂, —(CH₂)_(y)NHC(O)R^(o),—(CH₂)_(y)NHC(O)CH(V—R^(o))(R^(o)); wherein R^(o) is hydrogen, asubstituted or unsubstituted aliphatic group, an unsubstitutedheteroaryl or heterocyclic ring, phenyl (Ph), substituted Ph, —O(Ph),substituted —O(Ph), —CH₂(Ph), or substituted —CH₂(Ph); y is 0-6; and Vis a linker group. Examples of substituents on the aliphatic group orthe phenyl ring of R^(o) include amino, alkylamino, dialkylamino,aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano,carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, orhaloalkyl.

An aliphatic group or a non-aromatic heterocyclic ring may contain oneor more substituents. Examples of suitable substituents on the saturatedcarbon of an aliphatic group or of a non-aromatic heterocyclic ringinclude those listed above for the unsaturated carbon of an aryl orheteroaryl group and the following: ═O, ═S, ═NNHR*, ═NN(R*)₂, ═N—,═NNHC(O)R*, ═NNHCO₂(alkyl ), ═NNHSO₂(alkyl), or ═NR*, where each R* isindependently selected from hydrogen, an unsubstituted aliphatic groupor a substituted aliphatic group. Examples of substituents on thealiphatic group include amino, alkylamino, dialkylamino, aminocarbonyl,halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano,carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, orhaloalkyl.

Suitable substituents on the nitrogen of a non-aromatic heterocyclicring include —R⁺, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺, —C(O)C(O)R⁺, —C(O)CH₂C(O)R⁺,—SO₂R⁺, —SO₂N(R⁺)₂, —C(═S)N(R⁺)₂, —C(═NH)—N(R⁺)₂, and —NR⁺SO₂R⁺; whereinR⁺ is hydrogen, an aliphatic group, a substituted aliphatic group,phenyl (Ph), substituted Ph, —O(Ph), substituted —O(Ph), CH₂(Ph),substituted CH₂(Ph), or an unsubstituted heteroaryl or heterocyclicring. Examples of substituents on the aliphatic group or the phenyl ringinclude amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy,dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl,alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.

The term “linker group” or “linker” means an organic moiety thatconnects two parts of a compound. Linkers are typically comprised of anatom such as oxygen or sulfur, a unit such as —NH—, —CH₂—, —C(O)—,—C(O)NH—, or a chain of atoms, such as an alkylidene chain. Themolecular mass of a linker is typically in the range of about 14 to 200,preferably in the range of 14 to 96 with a length of up to about sixatoms. Examples of linkers include a saturated or unsaturated C₁₋₆alkylidene chain which is optionally substituted, and wherein one or twosaturated carbons of the chain are optionally replaced by —C(O)—,—C(O)C(O)—, —CONH—, —CONHNH—, —CO₂—, —OC(O)—, —NHCO₂—, —O—, —NHCONH—,—OC(O)NH—, —NHNH—, —NHCO—, —S—, —SO—, —SO₂—, —NH—, —SO₂NH—, or —NHSO₂—.

The term “alkylidene chain” refers to an optionally substituted,straight or branched carbon chain that may be fully saturated or haveone or more units of unsaturation. The optional substituents are asdescribed above for an aliphatic group.

A combination of substituents or variables is permissible only if such acombination results in a stable or chemically feasible compound. Astable compound or chemically feasible compound is one in which thechemical structure is not substantially altered when kept at atemperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

Compounds of formula I or salts thereof may be formulated intocompositions. In a preferred embodiment, the composition is apharmaceutical composition. In one embodiment, the composition comprisesan amount of the protein kinase inhibitor effective to inhibit a proteinkinase, particularly Aurora-2, in a biological sample or in a patient.In another embodiment, compounds of this invention and pharmaceuticalcompositions thereof, which comprise an amount of the protein kinaseinhibitor effective to treat or prevent an Aurora-2-mediated conditionand a pharmaceutically acceptable carrier, adjuvant, or vehicle, may beformulated for administration to a patient.

Another aspect of this invention relates to a method of treating orpreventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formula Ior a pharmaceutical composition thereof.

The term “Aurora-2-mediated condition” or “disease”, as used herein,means any disease or other deleterious condition in which Aurora isknown to play a role. The term “Aurora-2-mediated condition” or“disease” also means those diseases or conditions that are alleviated bytreatment with an Aurora-2 inhibitor. Such conditions include, withoutlimitation, cancer. The term “cancer” includes, but is not limited tothe following cancers: colon, breast, stomach, and ovarian.

Another aspect of the invention relates to inhibiting Aurora-2 activityin a biological sample, which method comprises contacting the biologicalsample with the Aurora-2 inhibitor of formula I, or a compositionthereof.

Another aspect of this invention relates to a method of inhibitingAurora-2 activity in a patient, which method comprises administering tothe patient a compound of formula I or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing a GSK-3-mediated disease with a GSK-3 inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula I or apharmaceutical composition thereof.

The term “GSK-3-mediated condition” or “disease”, as used herein, meansany disease or other deleterious condition or state in which GSK-3 isknown to play a role. Such diseases or conditions include, withoutlimitation, diabetes, Alzheimer's disease, Huntington's Disease,Parkinson's Disease, AIDS-associated dementia, amyotrophic lateralsclerosis (AML), multiple sclerosis (MS), schizophrenia, cardiomycetehypertrophy, reperfusion/ischemia, and baldness.

One aspect of this invention relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula I or apharmaceutical composition thereof. This method is especially-useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

Another aspect of the invention relates to inhibiting GSK-3 activity ina biological sample, which method comprises contacting the biologicalsample with a GSK-3 inhibitor of formula I.

Another aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, which method comprises administering to thepatient a compound of formula I or a composition comprising saidcompound.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that may beadministered to a patient, together with a compound of this invention,and which does not destroy the pharmacological activity thereof.

The term “patient” includes human and veterinary subjects.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; preparations of an enzymesuitable for in vitro assay; biopsied material obtained from a mammal orextracts thereof; and blood, saliva, urine, feces, semen, tears, orother body fluids or extracts thereof.

The amount effective to inhibit protein kinase, for example, Aurora-2and GSK-3, is one that measurably inhibits the kinase activity wherecompared to the activity of the enzyme in the absence of an inhibitor.Any method may be used to determine inhibition, such as, for example,the Biological Testing Examples described below.

Pharmaceutically acceptable carriers that may be used in thesepharmaceutical compositions include, but are not limited to, ionexchangers, alumina, aluminum stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

The compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously.

Sterile injectable forms of the compositions of this invention may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of this invention may beadministered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith or without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

In addition to the compounds of this invention, pharmaceuticallyacceptable derivatives or prodrugs of the compounds of this inventionmay also be employed in compositions to treat or prevent theabove-identified diseases or disorders.

A “pharmaceutically acceptable derivative or prodrug” means anypharmaceutically acceptable salt, ester, salt of an ester or otherderivative of a compound of this invention which, upon administration toa recipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. Particularly favored derivatives or prodrugs are thosethat increase the bioavailability of the compounds of this inventionwhen such compounds are administered to a patient (e.g., by allowing anorally administered compound to be more readily absorbed into the blood)or which enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies.

Pharmaceutically acceptable prodrugs of the compounds of this inventioninclude, without limitation, esters, amino acid esters, phosphateesters, metal salts and sulfonate esters.

Pharmaceutically acceptable salts of the compounds of this inventioninclude those derived from pharmaceutically acceptable inorganic andorganic acids and bases. Examples of suitable acid salts includeacetate, adipate, alginate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, citrate, camphorate, camphorsulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptanoate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, salicylate, succinate, sulfate, tartrate,thiocyanate, tosylate and undecanoate. Other acids, such as oxalic,while not in themselves pharmaceutically acceptable, may be employed inthe-preparation of salts useful as intermediates in obtaining thecompounds of the invention and their pharmaceutically acceptable acidaddition salts.

Salts derived from appropriate bases include alkali metal (e.g., sodiumand potassium), alkaline earth metal (e.g., magnesium), ammonium and N⁺(C₁₋₄ alkyl)₄ salts. This invention also envisions the quaternization ofany basic nitrogen-containing groups of the compounds disclosed herein.Water or oil-soluble or dispersible products may be obtained by suchquaternization.

The amount of the protein kinase inhibitor that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the patient treated and the particular mode of administration.Preferably, the compositions should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of the inhibitor can beadministered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of the inhibitor will also depend upon the particular compound inthe composition.

Depending upon the particular protein kinase-mediated condition to betreated or prevented, additional therapeutic agents, which are normallyadministered to treat or prevent that condition, may be administeredtogether with the inhibitors of this invention. For example, in thetreatment of cancer other chemotherapeutic agents or otheranti-proliferative agents may be combined with the Aurora-2 inhibitorsof this invention to treat cancer. These agents include, withoutlimitation, adriamycin, dexamethasone, vincristine, cyclophosphamide,fluorouracil, topotecan, taxol, interferons, and platinum derivatives.

Other examples of agents the inhibitors of this invention may also becombined with include, without limitation, agents for treating diabetessuch as insulin or insulin analogues, in injectable or inhalation form,glitazones, alpha glucosidase inhibitors, biguanides, insulinsensitizers, and sulfonyl ureas; anti-inflammatory agents such ascorticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide,and sulfasalazine; immunomodulatory and immunosuppressive agents such ascyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophophamide, azathioprine, and sulfasalazine;neurotrophic factors such as acetylcholinesterase inhibitors, MAOinhibitors, interferons, anti-convulsants, ion channel blockers,riluzole, and anti-Parkinsonian agents; agents for treatingcardiovascular disease such as beta-blockers, ACE inhibitors, diuretics,nitrates, calcium channel blockers, and statins; agents for treatingliver disease such as corticosteroids, cholestyramine, interferons, andanti-viral agents; agents for treating blood disorders such ascorticosteroids, anti-leukemic agents, and growth factors; and agentsfor treating immunodeficiency disorders such as gamma globulin.

Those additional agents may be administered separately from the proteinkinase inhibitor-containing composition, as part of a multiple dosageregimen. Alternatively, those agents may be part of a single dosageform, mixed together with the protein kinase inhibitor of this inventionin a single composition.

Compounds of this invention may exist in alternative tautomeric forms,as in tautomers i and ii shown below. Unless otherwise indicated, therepresentation of either tautomer is meant to include the other.

Preferred R^(x) groups, when present, include hydrogen, alkyl- ordialkylamino, acetamido, or a C₁₋₄ aliphatic group such as methyl,ethyl, cyclopropyl, or isopropyl.

Preferred R^(y) groups, when present, include Z-R^(3′) or an optionallysubstituted group selected from C₁₋₆ aliphatic, 5-6 memberedheterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein Z is amethylene and R^(3′) is —N(R⁴)₂, —OR, or an optionally substituted groupselected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10ring atoms, or a heterocyclyl ring having 5-10 ring atoms. PreferredR^(y) groups include 5-6 membered heteroaryl or heterocyclyl rings, suchas 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, orpiperazinyl; C₁₋₆ aliphatic, such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl; alkoxyalkylamino such as methoxyethylamino;,alkoxyalkyl such as methoxymethyl or methoxyethyl; alkyl- ordialkylamino such as ethylamino or dimethylamino; alkyl- ordialkylaminoalkoxy such as dimethylaminopropyloxy; acetamido; andoptionally substituted phenyl such as phenyl or halo-substituted phenyl.

R² and R^(2′) may be taken together to form a fused ring, thus providinga bicyclic ring system containing a pyrazole ring. Preferred fused ringsinclude benzo, pyrido, pyrimido, and a partially unsaturated 6-memberedcarbocyclo ring, wherein said fused ring is optionally substituted.These are exemplified in the following formula I compounds having apyrazole-containing bicyclic ring system:

Preferred substituents on the R²/R^(2′) fused ring include one or moreof the following: -halo, —N(R⁴)₂, —C₁₋₃ alkyl, —C₁₋₃ haloalkyl, —NO₂,—O(C₁₋₃ alkyl), —CO₂(C₁₋₃ alkyl), —CN, —SO₂ (C₁₋₃ alkyl), —SO₂NH₂,—OC(O)NH₂, —NH₂SO₂(C₁₋₃ alkyl), —NHC(O)(C₁₋₃ alkyl), —C(O)NH₂, and—CO(C₁₋₃ alkyl), wherein the (C₁₋₃ alkyl) is most preferably methyl.

When the pyrazole ring system is monocyclic, preferred R² groups includehydrogen, C₁₋₄ aliphatic, alkoxycarbonyl, (un)substituted phenyl,hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and(N-heterocyclyl)carbonyl. Examples of such preferred R² substituentsinclude methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl,cyclopentyl, phenyl, CO₂H, CO₂CH₃, CH₂OH, CH₂OCH₃, CH₂CH₂CH₂OH,CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂, CH₂CH₂CH₂NHCOOC(CH₃)₃,CONHCH(CH₃)₂, CONHCH₂CH═CH₂, CONHCH₂CH₂OCH₃, CONHCH₂Ph,CONH(cyclohexyl), CON(Et)₂, CON(CH₃)CH₂Ph, CONH(n-C₃H₇),CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON(n-C₃H₇)₂,CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl),CONHCH₃, CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH,CONH₂, and CO(piperidin-1-yl). A preferred R^(2′) group is hydrogen.

Preferred Q groups of formula I include —S—, —NH—, and —CH₂—. Morepreferred Q groups of formula I include —S— and —NH—.

Another embodiment of this invention relates to compounds of formulaII:.

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

-   Z¹ is nitrogen or CR⁸;-   R^(y) is Z-R^(3′) or an optionally substituted group selected from    C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10 ring    atoms, or a heterocyclyl ring having 5-10 ring atoms, or R^(y) and    R⁸ are taken together to form a fused, optionally substituted 5-7    membered, unsaturated or partially unsaturated, ring having 0-3 ring    heteroatoms selected from nitrogen, oxygen, or sulfur;-   Q is selected from —N(R⁴)—, —O—, —S—, or —CH(R⁶)—;-   R¹ is T-(Ring D);-   Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic    ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl,    said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms    selected from nitrogen, oxygen or sulfur, wherein each substitutable    ring carbon of Ring D is independently substituted by oxo, T-R⁵, or    V-Z-R⁵, and each substitutable ring nitrogen of Ring D is    independently substituted by —R⁴;-   T is a valence bond or a C₁₋₄ alkylidene chain, wherein when Q is    —CH(R⁶)—, a methylene unit of said C₁₋₄ alkylidene chain is    optionally replaced by —O—, —S—, —N(R⁴)—, —CO—, —CONH—, —NHCO—,    —SO₂—, —SO₂NH—, —NHSO₂—, —CO₂—, —OC(O)—, —OC(O)NH—, or —NHCO₂—;-   Z is a C₁₋₄ alkylidene chain;-   L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,    —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,    —N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,    —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,    —C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,    —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;-   R² and R^(2′) are independently selected from —R, -T-W—R⁶, or R² and    R^(2′) are taken together with their intervening atoms to form a    fused, 5-8 membered, unsaturated or partially unsaturated, ring    having 0-3 ring heteroatoms selected from nitrogen, oxygen, or    sulfur, wherein each substitutable ring carbon of said fused ring    formed by R² and R^(2′) is independently substituted by halo, oxo,    —CN, —NO₂, —R⁷, or —V—R⁶, and each substitutable ring nitrogen of    said ring formed by R² and R^(2′) is independently substituted by    R⁴;-   R^(3′) is selected from -halo, —OR, —C(═O)R, —CO₂R, —COCOR,    —COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,    —SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic),    —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,    —N(R⁴)SO₂R, —OC(═O)N(R⁷)₂, or an optionally substituted group    selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having    5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;-   each R is independently selected from hydrogen or an optionally    substituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a    heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring    having 5-10 ring atoms;-   each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂ (optionally    substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;-   each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,    —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,    —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted    C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,    —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;-   V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,    —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,    —N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,    —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,    —C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,    —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;-   W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,    —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,    —C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—,    —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,    —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;-   each R⁶ is independently selected from hydrogen or an optionally    substituted C₁₋₄ aliphatic group, or two R⁶ groups on the same    nitrogen atom are taken together with the nitrogen atom to form a    5-6 membered heterocyclyl or heteroaryl ring;-   each R⁷ is independently selected from hydrogen or an optionally    substituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen are    taken together with the nitrogen to form a 5-8 membered heterocyclyl    or heteroaryl ring; and-   R⁸ is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂,    —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,    —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic),    —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,    —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂; provided that when Q is —NH— and R^(y)    and R⁸ are taken together to form a fused ring, R¹ is other than a    pyrazol-3-yl ring or a pyrazol-3-yl-containing bicyclic ring system.

Another embodiment of this invention relates to compounds of formulaIIa:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

-   R^(y) is Z-R^(3′) or an optionally substituted group selected from    C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10 ring    atoms, or a heterocyclyl ring having 5-10 ring atoms;-   Q is selected from —N(R⁴)—, —O—, —S—, or —CH(R⁶)—;-   R¹ is T-(Ring D);-   Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic    ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl,    said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms    selected from nitrogen, oxygen or sulfur, wherein each substitutable    ring carbon of Ring D is independently substituted by oxo, T-R⁵, or    V-Z-R⁵, and each substitutable ring nitrogen of Ring D is    independently substituted by —R⁴;-   T is a valence bond or a C₁₋₄ alkylidene chain, wherein when Q is    —CH(R⁶)—, a methylene unit of said C₁₋₄ alkylidene chain is    optionally replaced by —O—, —S—, —N(R⁴)—, —CO—, —CONH—, —NHCO—,    —SO₂—, —SO₂NH—, —NHSO₂—, —CO₂—, —OC(O)—, —OC(O)NH—, or —NHCO₂—;-   Z is a C₁₋₄ alkylidene chain;-   L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,    —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,    —N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,    —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,    —C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,    —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;-   R² and R^(2′) are independently selected from —R, -T-W—R⁶, or R² and    R^(2′) are taken together with their intervening atoms to form a    fused, 5-8 membered, unsaturated or partially unsaturated, ring    having 0-3 ring heteroatoms selected from nitrogen, oxygen, or    sulfur, wherein each substitutable ring carbon of said fused ring    formed by R² and R^(2′) is independently substituted by halo, oxo,    —CN, —NO₂, —R⁷, or —V—R⁶, and each substitutable ring nitrogen of    said ring formed by R² and R^(2′) is independently substituted by    R⁴;-   R^(3′) is selected from -halo, —OR, —C(═O)R, —CO₂R, —COCOR,    —COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,    —SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic),    —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,    —N(R⁴)SO₂R, —OC(═O)N(R⁷)₂, or an optionally substituted group    selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having    5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;-   each R is independently selected from hydrogen or an optionally    substituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a    heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring    having 5-10 ring atoms;-   each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂ (optionally    substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;-   each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,    —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,    —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted    C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,    —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;-   V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,    —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,    —N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,    —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,    —C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,    —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;-   W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,    —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,    —C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N (R⁶)C(O)O—,    —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,    —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;-   each R⁶ is independently selected from hydrogen or an optionally    substituted C₁₋₄ aliphatic group, or two R⁶ groups on the same    nitrogen atom are taken together with the nitrogen atom to form a    5-6 membered heterocyclyl or heteroaryl ring; and-   each R⁷ is independently selected from hydrogen or an optionally    substituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen are    taken together with the nitrogen to form a 5-8 membered heterocyclyl    or heteroaryl ring.

Preferred R^(y) groups of formula IIa include Z-R^(3′) or an optionallysubstituted group selected from C₁₋₆ aliphatic, 5-6 memberedheterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein Z is amethylene and R^(3′) is —N(R⁴)₂, —OR, or an optionally substituted groupselected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10ring atoms, or a heterocyclyl ring having 5-10 ring atoms.

Examples of preferred R^(y) groups include 2-pyridyl, 4-pyridyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl,cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such asmethoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl,alkyl- or dialkylamino such as ethylamino or dimethylamino, alkyl- ordialkylaminoalkoxy such as dimethylaminopropyloxy, acetamido, optionallysubstituted phenyl such as phenyl or halo-substituted phenyl.

The R² and R^(2′) groups of formula IIa may be taken together to form afused ring, thus providing a bicyclic ring system containing a pyrazolering. Preferred fused rings include benzo, pyrido, pyrimido, and apartially unsaturated 6-membered carbocyclo ring. These are exemplifiedin the following formula IIa compounds having a pyrazole-containingbicyclic ring system:

Preferred substituents on the R²/R^(2′) fused ring of formula IIainclude one or more of the following: -halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl.

When the pyrazole ring system of formula IIa is monocyclic, preferred R²groups include hydrogen or a substituted or unsubstituted group selectedfrom aryl, heteroaryl, or a C₁₋₆ aliphatic group. Examples of suchpreferred R² groups include H, methyl, ethyl, propyl, cyclopropyl,i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

When Ring D of formula IIa is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula IIa is bicyclic, preferred bicyclic Ring D groupsinclude naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

On Ring D of formula IIa, preferred T-R⁵ or V-Z-R⁵ substituents include-halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group,—OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂(n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t-Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic)such as —NHMe, —N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic)such as —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl, and —CO₂(C₁₋₄ aliphatic).

Preferred formula IIa compounds have one or more, and more preferablyall, of the features selected from the group consisting of:

-   (a) R^(y) is Z-R^(3′) or an optionally substituted group selected    from C₁₋₆ aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6    membered heteroaryl, wherein Z is a methylene and R^(3′) is —N(R⁴)₂,    —OR, or an optionally substituted group selected from C₁₋₆    aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10 ring atoms, or    a heterocyclyl ring having 5-10 ring atoms;-   (b) R¹ is T-(Ring D), wherein T is a valence bond or a methylene    unit;-   (c) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic    aryl or heteroaryl ring; and-   (d) R² is —R or -T-W—R⁶ and R^(2′) is hydrogen, or R² and R^(2′) are    taken together to form an optionally substituted benzo ring.

More preferred compounds of formula IIa have one or more, and morepreferably all, of the features selected from the group consisting of:

-   (a) R^(y) is an optionally substituted group selected from C₁₋₆    aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered    heteroaryl;-   (b) R¹ is T-(Ring D), wherein T is a valence bond and Q is —S—,    —NH—, or —CH₂—;-   (c) Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic    aryl or heteroaryl ring; and-   (d) R² is —R and R^(2′) is hydrogen, wherein R is selected from    hydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or    a 5-6 membered heterocyclic ring.

Even more preferred compounds of formula IIa have one or more, and morepreferably all, of the features selected from the group consisting of:

-   (a) R^(y) is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl,    piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl,    isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or    dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally    substituted phenyl, or methoxymethyl;-   (b) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a    5-6 membered aryl or heteroaryl ring, wherein Ring D is optionally    substituted with one to two groups selected from -halo, —CN, —NO₂,    —N (R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR, —CO₂R,    —CONH(R⁴), —N (R⁴)COR, —N(R⁴)SO₂R, —N(R⁶)COCH₂CH₂N(R⁴)₂, or    —N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, and Q is —S— or —NH—; and-   (c) R² is hydrogen or a substituted or unsubstituted C₁₋₆ aliphatic,    and L is —O—, —S—, or —NH—. Representative compounds of formula IIa    are shown below in Table 1.

TABLE 1

IIa-1

IIa-2

IIa-3

IIa-4

IIa-5

IIa-6

IIa-7

IIa-8

IIa-9

IIa-10

IIa-11

IIa-12

IIa-13

IIa-14

IIa-15

In another embodiment, this invention provides a composition comprisinga compound of formula IIa and a pharmaceutically acceptable carrier.

Another aspect of this invention relates to a method of treating orpreventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIIa or a pharmaceutical composition thereof.

Another aspect of this invention relates to a method of inhibitingAurora-2 activity in a patient, which method comprises administering tothe patient a compound of formula IIa or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing a GSK-3-mediated disease with a GSK-3 inhibitor, which methodcomprises administering to a patient in need of such treatment atherapeutically effective amount of a compound of formula IIa or apharmaceutical composition thereof.

One aspect of this invention relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IIa or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

Another aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, which method comprises administering to thepatient a compound of formula IIa or a composition comprising saidcompound.

Another method relates to inhibiting Aurora-2 or GSK-3 activity in abiological sample, which method comprises contacting the biologicalsample with the Aurora-2 or GSK-3 inhibitor of formula IIa, or apharmaceutical composition thereof, in an amount effective to inhibitAurora-2 or GSK-3.

Each of the aforementioned methods directed to the inhibition ofAurora-2 or GSK-3, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula IIa, asdescribed above.

Another embodiment of this invention relates to compounds of formulaIIb:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

-   R^(y) is Z-R^(3′) or an optionally substituted group selected from    C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10 ring    atoms, or a heterocyclyl ring having 5-10 ring atoms, or R^(y) and    R⁸ are taken together to form a fused, optionally substituted 5-7    membered, unsaturated or partially unsaturated, ring having 0-3 ring    heteroatoms selected from nitrogen, oxygen, or sulfur;-   Q is selected from —N(R⁴)—, —O—, —S—, or —CH(R⁶)—;-   R¹ is T-(Ring D);-   Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic    ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl,    said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms    selected from nitrogen, oxygen or sulfur, wherein each substitutable    ring carbon of Ring D is independently substituted by oxo, T-R⁵, or    V-Z-R⁵, and each substitutable ring nitrogen of Ring D is    independently substituted by —R⁴;-   T is a valence bond or a C₁₋₄ alkylidene chain, wherein when Q is    —CH(R⁶)—, a methylene unit of said C₁₋₄ alkylidene chain is    optionally replaced by —O—, —S—, —N(R⁴)—, —CO—, —CONH—, —NHCO—,    —SO₂—, —SO₂NH—, —NHSO₂—, —CO₂—, —OC(O)—, —OC(O)NH—, or —NHCO₂—;-   Z is a C₁₋₄ alkylidene chain;-   L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,    —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,    —N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,    —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,    —C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,    —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;-   R² and R^(2′) are independently selected from —R, -T-W—R⁶, or R² and    R^(2′) are taken together with their intervening atoms to form a    fused, 5-8 membered, unsaturated or partially unsaturated, ring    having 0-3 ring heteroatoms selected from nitrogen, oxygen, or    sulfur, wherein each substitutable ring carbon of said fused ring    formed by R² and R^(2′) is independently substituted by halo, oxo,    —CN, —NO₂, —R⁷, or —V—R⁶, and each substitutable ring nitrogen of    said ring formed by R² and R^(2′) is independently substituted by    R⁴;-   R^(3′) is selected from -halo, —OR, —C(═O)R, —CO₂R, —COCOR,    —COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,    —SO₂N (R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic),    —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,    —N(R⁴)SO₂R, —OC(═O)N(R⁷)₂, or an optionally substituted group    selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having    5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;-   each R is independently selected from hydrogen or an optionally    substituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a    heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring    having 5-10 ring atoms;-   each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionally    substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;-   each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,    —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,    —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted    C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,    —N(R⁴)SO₂N (R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;-   V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,    —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,    —N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,    —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —C(R⁶)₂N    (R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,    —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;-   W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,    —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,    —C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—,    —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,    —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;-   each R⁶ is independently selected from hydrogen or an optionally    substituted C₁₋₄ aliphatic group, or two R⁶ groups on the same    nitrogen atom are taken together with the nitrogen atom to form a    5-6 membered heterocyclyl or heteroaryl ring;-   each R⁷ is independently selected from hydrogen or an optionally    substituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen are    taken together with the nitrogen to form a 5-8 membered heterocyclyl    or heteroaryl ring; and-   R⁸ is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂,    —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,    —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic),    —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,    —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂; provided that when Q is —NH— and R^(y)    and R⁸ are taken together to form a fused ring, R¹ is other than a    pyrazol-3-yl ring or a pyrazol-3-yl-containing bicyclic ring system.

Preferred R^(y) groups of formula IIb include Z-R^(3′) or an optionallysubstituted group selected from C₁₋₆ aliphatic, 5-6 memberedheterocyclyl, phenyl or 5-6 membered heteroaryl, wherein Z is amethylene and R^(3′) is —N(R⁴)₂, —OR, or an optionally substituted groupselected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10ring atoms, or a heterocyclyl ring having 5-10 ring atoms.

Examples of preferred R^(y) groups include 2-pyridyl, 4-pyridyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl,cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such asmethoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl,alkyl- or dialkylamino such as ethylamino or dimethylamino, alkyl- ordialkylaminoalkoxy such as dimethylaminopropyloxy, acetamido, optionallysubstituted phenyl such as phenyl or halo-substituted phenyl.

The R² and R^(2′) groups of formula IIb may be taken together to form afused ring, thus providing a bicyclic ring system containing a pyrazolering. Preferred fused rings include benzo, pyrido, pyrimido, and apartially unsaturated 6-membered carbocyclo ring. These are exemplifiedin the following formula IIb compounds having a pyrazole-containingbicyclic ring system:

Preferred substituents on the R²/R^(2′) fused ring of formula IIbinclude one or more of the following: -halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl.

When the pyrazole ring system of formula IIb is monocyclic, preferred R²groups include hydrogen or a substituted or unsubstituted group selectedfrom aryl, heteroaryl, or a C₁₋₆ aliphatic group. Examples of suchpreferred R² groups include H, methyl, ethyl, propyl, cyclopropyl,i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

When Ring D of formula IIb is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula IIb is bicyclic, preferred bicyclic Ring D groupsinclude naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

On Ring D of formula IIb, preferred T-R⁵ or V-Z-R⁵ substituents include-halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group,—OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂ (n-propyl), —NHSO₂ (isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t-Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic)such as —NHMe, —N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic)such as —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl, and —CO₂(C₁₋₄ aliphatic).

When R^(y) and R⁸ are taken together to form a fused ring, preferredrings formed by R^(y) and R⁸ include 5-6 membered unsaturated orpartially unsaturated rings having 0-2 heteroatoms. More preferred fusedrings formed by R^(y) and R⁸ include benzo, cyclohexo, and pyrido.

Preferred R⁸ groups of formula IIb, when present, include R, OR, andN(R⁴)₂. Examples of preferred R⁸ include methyl, ethyl, NH₂,NH₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂O, (piperidin-1-yl)CH₂CH₂O,and NH₂CH₂CH₂O.

Preferred formula IIb compounds have one or more, and more preferablyall, of the features selected from the group consisting of:

-   (a) R^(y) is Z-R^(3′) or an optionally substituted group selected    from C₁₋₆ aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6    membered heteroaryl, wherein Z is a methylene and R^(3′) is —N(R⁴)₂,    —OR, or an optionally substituted group selected from C₁₋₆    aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10 ring atoms, or    a heterocyclyl ring having 5-10 ring atoms;-   (b) R¹ is T-(Ring D), wherein T is a valence bond or a methylene    unit;-   (c) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic    aryl or heteroaryl ring; and-   (d) R2 is —R or -T-W—R⁶ and R^(2′) is hydrogen, or R² and R^(2′) are    taken together to form an optionally substituted benzo ring.

More preferred compounds of formula IIb have one or more, and morepreferably all, of the features selected from the group consisting of:

-   (a) R^(y) is an optionally substituted group selected from C₁₋₆    aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered    heteroaryl;-   (b) R¹ is T-(Ring D), wherein T is a valence bond, and Q is —S—,    —NH—, or —CH₂—;-   (c) Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic    aryl or heteroaryl ring; and-   (d) R² is —R and R^(2′) is hydrogen, wherein R is selected from    hydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or    a 5-6 membered heterocyclic ring.

Even more preferred compounds of formula IIb have one or more, and morepreferably all, of the features selected from the group consisting of:

-   (a) R^(y) is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl,    piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl,    isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or    dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally    substituted phenyl, or methoxymethyl, or R^(y) and R⁸ are taken    together to form a 5-6 membered unsaturated or partially unsaturated    ring having 0-2 heteroatoms selected from nitrogen, oxygen, or    sulfur;-   (b) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a    5-6 membered aryl or heteroaryl ring, wherein Ring D is optionally    substituted with one to two groups selected from -halo, —CN, —NO₂,    —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR, —CO₂R,    —CONH(R⁴), —N(R⁴)COR, —N(R⁴)SO₂R, —N(R⁶)COCH₂CH₂N(R⁴)₂, or    —N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, and Q is —S— or —NH—; and-   (c) R² is hydrogen or a substituted or unsubstituted C₁₋₆ aliphatic,    and L is —O—, —S—, or —NH—.

Representative compounds of formula IIb are shown below in Table 2.

TABLE 2

IIb-1

IIb-2

IIb-3

IIb-4

IIb-5

IIb-6

IIb-7

IIb-8

IIb-9

IIb-10

IIb-11

IIb-12

IIb-13

IIb-14

IIb-15

In another embodiment, this invention provides a composition comprisinga compound of formula IIb and a pharmaceutically acceptable carrier.

Another aspect of this invention relates to a method of treating orpreventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIIb or a pharmaceutical composition thereof.

Another aspect of this invention relates to a method of inhibitingAurora-2 activity in a patient, which method comprises administering tothe patient a compound of formula IIb or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing a GSK-3-mediated disease with a GSK-3 inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula IIb or apharmaceutical composition thereof.

One aspect of this invention relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IIb or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

Another aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, which method comprises administering to thepatient a compound of formula IIb or a composition comprising saidcompound.

Another method relates to inhibiting Aurora-2 or GSK-3 activity in abiological sample, which method comprises contacting the biologicalsample with the Aurora-2 or GSK-3 inhibitor of formula IIb, or apharmaceutical composition thereof, in an amount effective to inhibitAurora-2 or GSK-3.

Each of the aforementioned methods directed to the inhibition ofAurora-2 or GSK-3, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula IIb, asdescribed above.

Another embodiment of this invention relates to compounds of formulaIII:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

-   Z¹ is nitrogen or CR⁸, Z² is nitrogen or CH, and Z³ is nitrogen or    CR^(x), provided that one of Z¹ and Z³ is nitrogen;-   R^(x) is T-R³ or L-Z-R³;-   Q is selected from —N(R⁴)—, —O—, —S—, or —CH(R⁶)—;-   R¹ is T-(Ring D);-   Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic    ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl,    said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms    selected from nitrogen, oxygen or sulfur, wherein each substitutable    ring carbon of Ring D is independently substituted by oxo, T-R⁵, or    V-Z-R⁵, and each substitutable ring nitrogen of Ring D is    independently substituted by —R⁴;-   T is a valence bond or a C₁₋₄ alkylidene chain, wherein when Q is    —CH(R⁶)—, a methylene unit of said C₁₋₄ alkylidene chain is    optionally replaced by —O—, —S—, —N(R⁴)—, —CO—, —CONH—, —NHCO—,    —SO₂—, —SO₂NH—, —NHSO₂—, —CO₂—, —OC(O)—, —OC(O)NH—, or —NHCO₂—;-   Z is a C₁₋₄ alkylidene chain;-   L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,    —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,    —N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,    —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N (R⁶)—,    —C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,    —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;-   R² and R^(2′) are independently selected from —R, -T-W—R⁶, or R² and    R^(2′) are taken together with their intervening atoms to form a    fused, 5-8 membered, unsaturated or partially unsaturated, ring    having 0-3 ring heteroatoms selected from nitrogen, oxygen, or    sulfur, wherein each substitutable ring carbon of said fused ring    formed by R² and R^(2′) is independently substituted by halo, oxo,    —CN, —NO₂, —R⁷, or —V—R⁶, and each substitutable ring nitrogen of    said ring formed by R² and R^(2′) is independently substituted by    R⁴;-   R³ is selected from —R, -halo, —OR, —C(═O)R, —CO₂R, —COCOR,    —COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,    —SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic),    —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,    —N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;-   each R is independently selected from hydrogen or an optionally    substituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a    heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring    having 5-10 ring atoms;-   each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionally    substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;-   each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,    —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,    —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted    C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,    —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;-   V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,    —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,    —N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,    —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,    —C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,    —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;-   W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,    —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,    —C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—,    —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,    —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;-   each R⁶ is independently selected from hydrogen or an optionally    substituted C₁₋₄ aliphatic group, or two R⁶ groups on the same    nitrogen atom are taken together with the nitrogen atom to form a    5-6 membered heterocyclyl or heteroaryl ring;-   each R⁷ is independently selected from hydrogen or an optionally    substituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen are    taken together with the nitrogen to form a 5-8 membered heterocyclyl    or heteroaryl ring; and-   R⁸ is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂,    —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,    —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic),    —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,    —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂.

Accordingly, the present invention relates to compounds of formula IIIa,IIIb, IIIc and IIId as shown below:

Preferred R^(x) groups of formula III include T-R³ wherein T is avalence bond or a methylene and R³ is CN, —R, or —OR. When R³ is —R,preferred R³ groups include an optionally substituted group selectedfrom C₁₋₆ aliphatic, phenyl, or a 5-6 membered heteroaryl orheterocyclyl ring. When R³ is —OR, preferred R groups include anoptionally substituted group C₁₋₆ aliphatic group such as alkyl- ordialkylaminoalkyl and aminoalkyl. Examples of preferred R^(x) includeacetamido, CN, piperidinyl, piperazinyl, phenyl, pyridinyl,imidazol-1-yl, imidazol-2-yl, cyclohexyl, cyclopropyl, methyl, ethyl,isopropyl, t-butyl, NH₂CH₂CH₂NH, and NH₂CH₂CH₂O.

Preferred R⁸ groups of formula III, when present, include R, OR, andN(R⁴)₂. Examples of preferred R⁸ include methyl, ethyl, NH₂,NH₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂O, (piperidin-1-yl)CH₂CH₂O,and NH₂CH₂CH₂O.

The R² and R^(2′) groups of formula III may be taken together to form afused ring, thus providing a bicyclic ring system containing a pyrazolering. Preferred fused rings include benzo, pyrido, pyrimido, and apartially unsaturated 6-membered carbocyclo ring. These are exemplifiedin the following formula III compounds having a pyrazole-containingbicyclic ring system:

Preferred substituents on the formula III R²/R^(2′) fused ring includeone or more of the following: -halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl.

When the pyrazole ring system of formula III is monocyclic, preferred R²groups include hydrogen or a substituted or unsubstituted group selectedfrom aryl, heteroaryl, or a C₁₋₆ aliphatic group. Examples of suchpreferred R² groups include H, methyl, ethyl, propyl, cyclopropyl,i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

When Ring D of formula III is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula III is bicyclic, preferred bicyclic Ring D groupsinclude naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

On Ring D of formula III, preferred T-R⁵ or V-Z-R⁵ substituents include-halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group,—OR, —C(O)R, —CO₂R, —CON(R⁴)₂, —OCO(R⁴)₂, —N(R⁴)COR, —N(R⁴)CO₂R,—SO₂N(R⁴)₂, —N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂(n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t-Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic)such as —NHMe, —N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic)such as —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl, and —CO₂(C₁₋₄ aliphatic).

Preferred compounds of formula IIIa, IIIb, IIIc, or IIId have one ormore, and more preferably all, of the features selected from the groupconsisting of:

-   (a) R^(x) is hydrogen, alkyl- or dialkylamino, acetamido, or a C₁₋₄    aliphatic group;-   (b) R¹ is T-(Ring D), wherein T is a valence bond or a methylene    unit;-   (c) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic    aryl or heteroaryl ring; and-   (d) R² is —R or -T-W—R⁶ and R^(2′) is hydrogen, or R² and R^(2′) are    taken together to form an optionally substituted benzo ring.

More preferred compounds of formula IIIa, IIIb, IIIc, or IIId have oneor more, and more preferably all, of the features selected from thegroup consisting of:

-   (a) R¹ is T-(Ring D), wherein T is a valence bond, and Q is —S—,    —NH—, or —CH₂—;-   (b) Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic    aryl or heteroaryl ring; and-   (c) R² is —R and R^(2′) is hydrogen, wherein R is selected from    hydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or    a 5-6 membered heterocyclic ring.

Even more preferred compounds of formula IIIa, IIIb, IIIc, or IIId haveone or more, and more preferably all, of the features selected from thegroup consisting of:

-   (a) R^(x) is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl,    methylamino or acetimido;-   (b) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a    5-6 membered aryl or heteroaryl ring, wherein Ring D is optionally    substituted with one to two groups selected from -halo, —CN, —NO₂,    —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR, —CO₂R,    —CON(R⁴)₂, —OCO(R⁴)₂, —N(R⁴)COR, —N(R⁴)SO₂R, —N(R⁶)COCH₂CH₂N(R⁴)₂,    or —N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, and Q is —S— or —NH—; and-   (c) R² is hydrogen or a substituted or unsubstituted C₁₋₆ aliphatic.

Representative compounds of formula III are shown below in Table 3.

TABLE 3

III-1 III-2 III-3

III-4 III-5 III-6

III-7 III-8 III-9

III-10 III-11 III-12

III-13 III-14 III-15

III-16 III-17 III-18

III-19 III-20 III-21

III-22 III-23 III-24

III-25 III-26 III-27

III-28 III-29 III-30

In another embodiment, this invention provides a composition comprisinga compound of formula III and a pharmaceutically acceptable carrier.

Another aspect of this invention relates to a method of treating orpreventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIII or a pharmaceutical composition thereof.

Another aspect of this invention relates to a method of inhibitingAurora-2 activity in a patient, which method comprises administering tothe patient a compound of formula III or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing a GSK-3-mediated disease with a GSK-3 inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula III or apharmaceutical composition thereof.

One aspect of this invention relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula III or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

Another aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, which method comprises administering to thepatient a compound of formula III or a composition comprising saidcompound.

Another method relates to inhibiting Aurora-2 or GSK-3 activity in abiological sample, which method comprises contacting the biologicalsample with the Aurora-2 or GSK-3 inhibitor of formula III, or apharmaceutical composition thereof, in an amount effective to inhibitAurora-2 or GSK-3.

Each of the aforementioned methods directed to the inhibition ofAurora-2 or GSK-3, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula III asdescribed above.

The compounds of this invention may be prepared in general by methodsknown to those skilled in the art for analogous compounds, asillustrated by the general Schemes I-VII.

Scheme I above shows a general route for the preparation of compounds offormula IIb. The dichloro intermediate 1 (prepared using methods similarto those reported in J. Indian. Chem. Soc., 61, 690-693 (1984) or in J.Med. Chem., 37, 3828-3833 (1994)) is sequentially reacted with twonucleophiles: R¹-QH to displace the chloride at position 4 to affordintermediate 2; and then 2 is treated with an aminopyrazole (oraminoindazole) to displace the chloride at position 2, using proceduressimilar to those described in J. Med. Chem, 38, 14, 2763-2773, (1995) toafford compounds of formula IIb.

Scheme II above shows a general route for the preparation of compoundsof formula IIb wherein Q is an N, O or S linker and R^(y) is a groupattached to the pyrimidine core via a heteroatom. Starting material4,6-dihydroxy-2-methylsulfanylpyrimidine (4) is prepared usingprocedures similar to those reported in J. Med. Chem., 27, 12, 1621-1629(1984). Chlorination of 4 with POCl₃ affords the dichloro intermediate5. The two chlorides of 5 are sequentially displaced with theappropriate R¹-QH, to afford compound 6, and then with R^(y)—H (amine,alcohol, or thiol) to afford compound 7 using procedures similar tothose reported in U.S. Pat. No. 2,585,906. Alternatively, the order ofdisplacement may be reversed by first displacing with RY-H and then withR¹-QH. The methyl sulfanyl group of compound 7 is then oxidized (forexample, with oxone) to afford compound 8 and the resultingmethylsulfonyl is finally displaced with the amino moiety ofaminopyrazole (or aminoindazole) by methods substantially similar tothose described above for Scheme 1 step (b) to afford compounds offormula IIb.

Scheme III above shows a general route for the preparation of compoundsof formula IIa. The three chlorides of starting material 8 aresequentially displaced with (a) the amino moiety of aminopyrazole (oraminoindazole) to afford compound 9, (b) the R¹-QH group to affordcompound 10, and (c) R^(y)—H (amine, alcohol, or thiol) using proceduressimilar to the ones reported in J. Indian Chem. Soc., 53, 207-208,(1976) to afford compounds of formula IIa. These three steps can also beperformed in different order to afford compounds of formula IIa.

Scheme IV above shows a general route for the preparation of compoundsof formula IIIa. Treatment of 11 with aminopyrazole (or aminoindazole)to provide 12 may be performed in a manner similar to that described inHeterocycles, 51, 5, 1999, 1035-1050. The intermediate 13 is obtained bydisplacement with R¹-QH in a manner similar to that described inFarmaco. Ed. Sci., 27, 1972, 591-600. For the preparation of compoundsof formula IIIa where R^(x) is hydrogen, the chlorine may be removed byreduction. Alternatively, for the preparation of compounds of formulaIIIa where R^(x) is other than hydrogen, the chlorine may be displacedby methods known to those skilled in the art to afford compounds with avariety of R^(x) substituents.

Scheme V above shows a general route for the preparation of thecompounds of formula IIIb. Displacement of the bromide with R¹-QH toafford compound 15 may be performed in a manner similar to thatdescribed in Heterocycles, 51, 5, 1999, 1035-1050. Displacement of thechlorines may be carried out sequentially as described above.

Scheme VI above shows a general route for the preparation of thecompounds of formulae IIIc and IIId. The displacement with aminopyrazole(or aminoindazole) followed by the displacement with R¹-QH may beperformed in a manner similar to that described in Indian J. Chem. Sect.B, 29, 5, 1990, 435-439.

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

BIOLOGICAL TESTING

The activity of the compounds as protein kinase inhibitors may beassayed in vitro, in vivo or in a cell line. In vitro assays includeassays that determine inhibition of either the phosphorylation activityor ATPase activity of the activated protein kinase. Alternate in vitroassays quantitate the ability of the inhibitor to bind to the proteinkinase. Inhibitor binding may be measured by radiolabelling theinhibitor prior to binding, isolating the inhibitor/protein kinasecomplex and determining the amount of radiolabel bound. Alternatively,inhibitor binding may be determined by running a competition experimentwhere new inhibitors are incubated with the protein kinase bound toknown radioligands.

BIOLOGICAL TESTING EXAMPLE 1 K_(i) Determination for the Inhibition ofGSK-3

Compounds are screened for their ability to inhibit GSK-3β (AA 1-420)activity using a standard coupled enzyme system (Fox et al. (1998)Protein Sci. 7, 2249). Reactions are carried out in a solutioncontaining 100 mM HEPES (pH 7.5), 10 mM MgCl₂, 25 mM NaCl, 300 μM NADH,1 mM DTT and 1.5% DMSO. Final substrate concentrations in the assay are20 μM ATP (Sigma Chemicals, St Louis, Mo.) and 300 μM peptide(HSSPHQS(PO₃H₂)EDEEE, American Peptide, Sunnyvale, Calif.). Reactionsare carried out at 30° C. and 20 nM GSK-3β. Final concentrations of thecomponents of the coupled enzyme system are 2.5 mM phosphoenolpyruvate,300 μM NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactatedehydrogenase.

An assay stock buffer solution is prepared containing all of thereagents listed above with the exception of ATP and the test compound ofinterest. The assay stock buffer solution (175 μl) is incubated in a 96well plate with 5 μl of the test compound of interest at finalconcentrations spanning 0.002 μM to 30 μM at 30° C. for 10 min.Typically, a 12 point titration is conducted by preparing serialdilutions (from 10 mM compound stocks) with DMSO of the test compoundsin daughter plates. The reaction is initiated by the addition of 20 μlof ATP (final concentration 20 μM). Rates of reaction are obtained usinga Molecular Devices Spectramax plate reader (Sunnyvale, Calif.) over 10min at 30° C. The K_(i) values are determined from the rate data as afunction of inhibitor concentration.

BIOLOGICAL TESTING EXAMPLE 2 K_(i) Determination for the Inhibition ofAurora-2

Compounds are screened in the following manner for their ability toinhibit Aurora-2 using a standard coupled enzyme assay (Fox et al (1998)Protein Sci 7, 2249).

To an assay stock buffer solution containing 0.1M HEPES 7.5, 10 mMMgCl₂, 1 mM DTT, 25 mM NaCl, 2.5 mM phosphoenolpyruvate, 300 mM NADH, 30mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 40 mM ATP, and800 μM peptide (LRRASLG, American Peptide, Sunnyvale, Calif.) is added aDMSO solution of a compound of the present invention to a finalconcentration of 30 μM. The resulting mixture is incubated at 30° C. for10 min. The reaction is initiated by the addition of 10 μL of Aurora-2stock solution to give a final concentration of 70 nM in the assay. Therates of reaction are obtained by monitoring absorbance at 340 nm over a5 minute read time at 30° C. using a BioRad Ultramark plate reader(Hercules, Calif.). The K_(i) values are determined from the rate dataas a function of inhibitor concentration.

While we have presented a number of embodiments of this invention, it isapparent that our basic construction can be altered to provide otherembodiments which utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments which have been represented by way of example.

1. A compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein: Z¹ is CR⁸; R^(y)is Z-R^(3′) or an optionally substituted group selected from C₁₋₆aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10 ring atoms, or aheterocyclyl ring having 5-10 ring atoms, or R^(y) and R⁸ are takentogether to form a fused, optionally substituted benzo ring; Q isselected from —N(R⁴)—, —O—, —S—, or —CH(R⁶)—; R¹ is T-(Ring D); Ring Dis a 6-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein each substitutable ring carbonof Ring D is independently substituted by oxo, T-R⁵, or V-Z-R⁵, and eachsubstitutable ring nitrogen of Ring D is independently substituted by—R⁴; T is a valence bond or a C₁₋₄ alkylidene chain, wherein when Q is—CH(R⁶)—, a methylene unit of said C₁₋₄ alkylidene chain is optionallyreplaced by —O—, —S—, —N(R⁴)—, —CO—, —CONH—, —NHCO—, —SO₂—, —SO₂NH—,—NHSO₂—, —CO₂—, —OC(O)—, —OC(O)NH—, or —NHCO₂—; Z is a C₁₋₄ alkylidenechain; R² and R^(2′) are independently selected from —R, -T-W—R⁶, or R²and R^(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ring having0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, whereineach substitutable ring carbon of said fused ring formed by R² and R²′is independently substituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, andeach substitutable ring nitrogen of said ring formed by R² and R^(2′) isindependently substituted by R⁴; R^(3′) is selected from -halo, —OR,—C(═O)R, —CO₂R, —COCOR, —COCH₂COR, —NO₂, —CN,—S(O)R, —S(O)₂R, —SR,—N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, C═N—OR, —N(R⁷)CON(R⁷)₂,—N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, —OC(═O)N(R⁷)₂, or an optionally substitutedgroup selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each Ris independently selected from hydrogen or an optionally substitutedgroup selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R⁴is independently selected from —R⁷, —COR⁷, —CO₂(optionally substitutedC₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷; each R⁵ is independently selectedfrom —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R,—SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR,—N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁴)₂; V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—,—N(R⁶)—, —CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—,—N(R⁶)SO₂N(R⁶)—, —N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—,—C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—; W is—C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—; each R⁶ is independently selected from hydrogen or anoptionally substituted C₁₋₄ aliphatic group, or two R⁶ groups on thesame nitrogen atom are taken together with the nitrogen atom to form a5-6 membered heterocyclyl or heteroaryl ring; each R⁷ is independentlyselected from hydrogen or an optionally substituted C₁₋₆ aliphaticgroup, or two R⁷ on the same nitrogen are taken together with thenitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and R⁸is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN,—S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR,—N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁴)₂; provided that when Q is —NH— and R^(y) and R⁸ are takentogether, R¹ is other than pyrazol-3-yl or a bicyclic ring systemcontaining said pyrazol-3-yl ring.
 2. The compound according to claim 1,wherein said compound has one or more features selected from the groupconsisting of: (a) R^(y) is Z-R^(3′) or an optionally substituted groupselected from C₁₋₆ aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6membered heteroaryl, wherein Z is a methylene and R^(3′) is —N(R⁴)₂,—OR, or an optionally substituted group selected from C₁₋₆ aliphatic,C₁₋₁₀ aryl a heteroaryl ring having 5-10 ring atoms, or a heterocyclylring having 5-10 ring atoms; (b) R¹ is T-(Ring D), wherein T is avalence bond or a methylene unit; (c) Ring D is a 6-7 memberedmonocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and (d)R² is —R or -T-W—R⁶ and R^(2′) is hydrogen, or R² and R^(2′) are takentogether to form an optionally substituted benzo ring.
 3. The compoundaccording to claim 2, wherein: (a) R^(y) is Z-R^(3′) or an optionallysubstituted group selected from C₁₋₆ aliphatic, 5-6 memberedheterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein Z is amethylene and R^(3′) is —N(R⁴)₂, —OR, or an optionally substituted groupselected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10ring atoms, or a heterocyclyl ring having 5-10 ring atoms; (b) R¹ isT-(Ring D), wherein T is a valence bond or a methylene unit; (c) Ring Dis a 6-7 membered monocyclic or an 8-10 membered bicyclic aryl orheteroaryl ring; and (d) R² is —R or -T-W—R⁶ and R^(2′) is hydrogen, orR² and R^(2′) are taken together to form an optionally substituted benzoring.
 4. The compound according to claim 2, wherein said compound hasone or more features selected from the group consisting of: (a) R^(y) isan optionally substituted group selected from C₁₋₆ aliphatic, 5-6membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; (b) R¹ isT-(Ring D), wherein T is a valence bond, and Q is —S—, —NH—, or —CH2—;(c) Ring D is a 6 membered monocyclic or an 8-10 membered bicyclic arylor heteroaryl ring; and (d) R² is —R and R^(2′) is hydrogen, wherein Ris selected from hydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 memberedheteroaryl ring, or a 5-6 membered heterocyclic ring.
 5. The compoundaccording to claim 4, wherein: (a) R^(y) is an optionally substitutedgroup selected from C₁₋₆ aliphatic, 5-6 membered heterocyclyl, phenyl,or 5-6 membered heteroaryl; (b) R¹ is T-(Ring D), wherein T is a valencebond, and Q is —S—, —NH—, or —CH₂—; (c) Ring D is a 6 memberedmonocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and (d)R² is —R and R^(2′) is hydrogen, wherein R is selected from hydrogen,C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6membered heterocyclic ring.
 6. The compound according to claim 4,wherein said compound has one or more features selected from the groupconsisting of: (a) R^(y) is selected from 2-pyridyl, 4-pyridyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl,cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl-or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionallysubstituted phenyl, or methoxymethyl, or R^(y) and R⁸ are taken togetherto form a benzo ring; (b) R¹ is T-(Ring D), wherein T is a valence bondand Ring D is a 6 membered aryl or heteroaryl ring, wherein Ring D isoptionally substituted with one to two groups selected from -halo, —CN,—NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR, —CO₂R,—CONH(R⁴), —N(R⁴)COR, —N(R⁴)SO₂R, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(F⁶)COCH₂CH₂CH₂N(R⁴)₂, and Q is —S— or —NH—; and (c) R² is hydrogen ora substituted or unsubstituted C₁₋₆ aliphatic.
 7. The compound accordingto claim 6, wherein: (a) R^(y) is selected from 2-pyridyl, 4-pyridyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl,cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl-or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionallysubstituted phenyl, or methoxymethyl; or R^(y) and R⁸ are taken togetherto form benzo ring; (b) R¹ is T-(Ring D), wherein T is a valence bondand Ring D is a 6 membered aryl or heteroaryl ring, wherein Ring D isoptionally substituted with one to two groups selected from -halo, —CN,—NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR, —CO₂R,—CONH(R⁴), —N(R⁴)COR, —N(R⁴)SO₂R, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, and Q is —S—or —NH—; and (c) R² is hydrogen ora substituted or unsubstituted C₁₋₆ aliphatic.
 8. A compound selectedfrom the group consisting of:6-Benzyl-N⁴-(1H-indazol-6-yl)-N²(5-methyl-1H-pyrazol-3-yl)-pyrimidine-2,4-diamine;6-Methyl-N²-(5-methyl-1H-pyrazol-3-yl)-N⁴-pyridine-3-ylmethyl-pyrimidine-2,4-diamine;N-(4-{2-(5-Methyl-1H-pyrazol-3-ylamino)-6-[(pyridin-3-ylmethyl)-amino]-pyrimidin-4-ylamino}-phenyl)-methanesulfonamide;N²-(5-Cyclopropyl-1H-pyrazol-3-yl)-N⁴-(2-methoxy-ethyl)-6-(thiophen-2-ylmethylsulfanyl)-pyrimidine-2,4-diamine;[4-(Benzothiazol-6-ylsulfanyl)-6-(3-dimethylamino-propoxy)-pyrimidine-2-yl]-(5-cyclopropyl-1H-pyrazol-3-yl)-amine;N-(4-[2-{5-Cyclopropyl-1H-pyrazol-3-ylamino)-6-(1-methyl-piperidin-4-yloxy)-pyrimidin-4-ylsulfanyl]-phenyl}-acetamide;N-{4-[2-(5-Methyl-1H-pyrazol-3-ylamino)-quinazolin-4-ylsulfanyl]-phenyl}-acetamide;[4-(Benzothiazol-6-ylsulfanyl)-quinazolin-2-yl-(5-methyl1H-pyrazol-3-yl)-amine;{4-[2-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-quinazolin-4-yloxy]-phenyl}-acetonitrile;(5-Cyclopropyl-1H-pyrazol-3-yl)-[4-(3-methoxy-benzyl)-quinazolin-2-yl]-amine;N²-(1H-Indazol-6-yl)-N⁴-pyridin-3-ylmethyl-quinazoline-2,4-diamine; and(4-(Benzyloxy-quinazolin-2-yl-(1H-indazol-3-yl)-amine.
 9. A compositioncomprising a compound according to anyone of claims 1-8, arid apharmaceutically acceptable carrier.
 10. The composition according toclaim 9, further comprising an additional therapeutic agent.